N,N-dimethyldiatrizoic acid and its conjugates as hepatobiliary agents for x-ray CT imaging

ABSTRACT

Compounds having formulae I, II or/III, or pharmaceutically acceptable salts thereof,                    
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are the same or different and are hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or carboxamido alkyl with the proviso that in formula I R 2  and R 3  cannot be methyl; and 
     m, n and p are the same or different and are 0-24 with the proviso that m+n≦24, are useful as contrast agents in x-ray imaging compositions and methods.

This application is a divisional of application Ser. No. 09/273,522filed on Mar. 22, 1999, now U.S. Pat. No. 6,051,210 which in turn is acontinuation of application Ser. No. 08/856,796 filed on May 15, 1997now abandoned.

BACKGROUND OF THE INVENTION

1. Filed of the Invention

This invention relates to compositions containing conjugates ofN,N-dimethyldiatrizoic acid and methods for their use in diagnosticradiology. More particularly, the invention relates to compositionscontaining N,N-dimethyldiatrizoic acid or a conjugate thereof for use ashepatobiliary agents for x-ray CT imaging.

2. Reported Developments Roentgenographic examination utilizing X-raysand computed tomography (hereinafter CT) scans of fractures and otherconditions associated with the skeletal system is routinely practicedwithout the use of contrast agents. X-ray visualization of organscontaining soft tissues, such as the gastrointestinal tract, heart,lung, kidneys and spleen, requires the use of contrast agents whichattenuate x-ray radiation. D. P. Swanson et al. in “Pharmaceuticals InMedical Imaging”, 1990, MacMillan Publishing Company, provides anexcellent background in medical imaging utilizing contrast agents andcompositions therewith.

Roentgenographic examination of the GI tract are indicated forconditions of digestive disorders, changes in bowel habit, abdominalpain, GI bleeding and the like. Prior to radiological examination,administration of a radiopaque contrast medium is necessary to permitadequate delineation of the respective lumen or mucosal surface fromsurrounding soft tissues. Accordingly, a contrast medium is administeredorally to visualize the mouth, pharynx, esophagus, stomach, duodenum andproximal small intestine. The contrast medium is administered rectallyfor examination of the distal small intestine and the colon.

The most widely used contrast agent for the visualization of the GItract is barium sulfate administered as a suspension orally or rectallyas an enema. (See, for example, U.S. Pat. Nos. 2,659,690; 2,680,089;3,216,900; 3,235,462; 4,038,379; and 4,120,946.) Notwithstanding itsrelatively good contrast characteristics, negligible absorption from theGI tract following oral or rectal administration and speedy excretionform the body, barium sulfate has certain disadvantages. In the presenceof intestinal fluids it lacks homogeneity and poorly adheres to mucusmembranes which can result in poor x-ray images. In the colon, whenadministered as an enema, it flocculates and forms irregular clumps withfecal matter.

In addition to, or in place of barium sulfate, iodinated organiccompounds have also been used as GI contrast agents since the iodineatom is an effective x-ray absorber. They have the most versatility andare utilized in the widest variety of procedures. They are veryabsorptive of x-rays with which the iodine interacts and produce aso-called photoelectric effect which is a large magnification incontrast caused by the photons stopped in the iodine-containing medium.The magnification of contrast exceeds the level that would be expectedfrom relative changes in density. Because of this magnification,relatively low concentrations of the contrast agents can be utilized.(For iodinated agents see, for example, U.S. Pat. Nos.: 2,786,055;3,795,698; 2,820,814; 3,360,436; 3,574,718; 3,733,397; 4,735,795;5,047,228; 5,308,607; 5,310,538; 5,318,769; 5,334,370; 5,336,484 and5,344,638.)

The desiderata for an ideal GI contrast agent includes: goodtoxicological profile; the ability to fill the entire bowel/lumen andevenly coat the gut mucosa so that the presence of the bowel isdetectable when the lumen is not distended; nonirritation to theintestinal mucosa; and passage through the GI tract without producingartifacts or stimulating vigorous intestinal peristalsis.

We have found that the compounds of the present invention having theseand other desirable characteristics in the GI tract do satisfy therequirements of an x-ray contrast agent when incorporated in suitableaqueous oral or rectal formulations for examination of the GI tractutilizing x-rays and CT scans.

During extensive investigation we have also discovered that thecompounds of the present invention are eminently suitable forintravenous administration for CT imaging of organs, such as the kidneysand liver. It is well known by those skilled in the art that agents forintravenous administration must meet certain requirements that arc morestringent than the requirements for oral and rectal administration sincethe agents are directly introduced into the blood stream of the patient.The imagining of the organ or body section is accomplished by means ofroentgenography commonly referred to as computed tomography (CT) orcomputerized axial tomography (CAT) in which the emergent x-ray beam ismeasured by a scintillation counter, the electronic impulses arerecorded on a magnetic disk, and then processed by a computer forreconstruction display.

SUMMARY OF THE INVENTION

In one aspect the present invention provides hepatobiliary agents forx-ray CT imaging having the formula I, II or III, or a pharmaceuticallyacceptable salt thereof:

R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are the same or different and arehydrogen, alkyl, cycloalkyl, aralkyl, aryl, haloalkyl, hydroxyalkyl,alkoxyalkyl, carboxyalkyl or carboxamido alkyl; and

m, n and p are the same or different and are 0-24 with the proviso thatm+n≦24.

The terms herein throughout the specification and the claims have thefollowing meaning.

The term “alkyl” refers to both straight, and branched, unsubstitutedchains of 1 to 10 carbon atoms. Those chains having 1 to 5 carbon atomsare preferred. Methyl is the most preferred alkyl group.

The term “cycloalkyl” refers to cyclic hydrocarbon groups of 3 to 7carbon atoms. The groups may be unsubstituted or substituted by, forexample, alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, alkanoyl,alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol,alkylthiol, nitro, cyano, carboxy, carbamoyl, alkoxycarbonyl,alkylsulfonyl, sulfonamido and the like.

The term “aryl” refers to phenyl, pyridyl, furanyl, thiophenyl,pyrrolyl, imidazolyl and the like, all of which may be substituted.Preferred substituted aryl groups are those substituted with 1, 2 or 3halogen, nitroamino, maleimido, isothiocyanato, hydroxy, hydroxyalkyl,alkyl, alkoxy, carbamoyl, carboxamide, acylamino or carboxy moieties.

The term “aralkyl” refers to an aryl group bonded through an alkylgroup.

The term “halo” refers to bromo, chloro, fluoro or iodo.

The term “alkoxy” refers to a chain consisting of C and O atoms of a 2:1ratio in the range of 4 to 10 atoms, wherein methoxy is the mostpreferred alkoxy group.

The term “carboxy” refers to the group —C(O)OH or the group —C(O)ORwherein R is alkyl.

The compounds or pharmaceutically acceptable salts thereof incorporatedin a suitable pharmaceutically acceptablc vehicle, such as human serumalbumin, and administered to a mammal intravenously, provide sufficientiodine concentration in the liver and other organs for x-ray CT imagingat dose levels of 5 mmol/kg of body weight or higher.

There is further provided a method for x-ray CT diagnostic imaging ofthe liver and/or other organs which comprises intravenouslyadministering to the patient an effective contrast producing amount ofthe x-ray contrast composition comprising a compound of formula I, II orIII.

In another aspect the present invention provides an x-ray contrastcomposition for diagnostic imagining of the GI tract by x-rays or CTscans wherein the composition comprises in a pharmaceutically acceptableaqueous carrier the compounds of the formula I, II or III, or apharmaceutically acceptable salt thereof.

There is further provided a method for x-ray diagnostic imaging of theGI tract which comprises orally or rectally administering to the patientan effective contrast producing amount of the x-ray contrastcomposition.

DETAILED DESCRIPTION OF THE INVENTION

Some starting materials/reagents used in the synthesis of the compoundsof the present invention are readily available, while others can be madeby methods known in the art.

The compounds of the present invention were synthesized as shown in thefollowing schemes.

The compound of formula I, N,N-Dimethyldiatrizoic acid (I′) (hereinaftersometimes referred to as MDTA) was synthesized, as in reference H.Holtermann et al., U.S. Pat. No. 3,178,673, Apr. 13, 1965, by theN-methylation of diatrizoic acid (IV) using either methyl iodide ordimethyl sulfate in aqueous media at alkaline pH to obtain pure MDTA(>99.9% purity) as a white crystalline solid (m.p. 185° C.). Watersolubility of the sodium salt was ˜0.35 M. The solubility of theN-methyl-glucamine (NMG) salt was ˜1.3 M.

Compounds of formula II (A), (hereinafter sometimes referred to as fattyacid conjugates or analogs of P-MDTA or FA-PMDTA).

R₁, R₂, R₃, R₄, R₆ and n are as defined above, and the compounds weremade as shown in Scheme 1.

MDTA-chloride (X) was made by treating MDTA (I′) with thionyl chlorideunder reflux for 24 h.

The compounds of formula II were prepared by reaction of (4-aminophenyl)alkanoic esters (IX) with MDTA-chloride (X) in dimethylacetamide(hereinafter sometimes referred to as DMA).

In Scheme 1 specific values are denoted for n and x relating to thecompounds of the illustrative working examples; however, it is to beunderstood that the values of n and x include the range of 0 to 24 andthe alkanoic esters are attached to the ortho, meta or para positions ofthe amino phenyl moiety. In Scheme 1 and in working examples theabbreviation “h” denotes hour or hours, and “RT” denotes roomtemperature.

Referring to Scheme 1, ω-Bromoalkanoic acids V were converted to thecorresponding phosphonium salts which when subjected to Wittig reactionwith p-nitrocinnamaldehyde VI in presence of potassium t-butoxide gavethe Wittig products VII. No attempts were made to separate the dienemixture. The carboxylic acid group in VII was protected as its t-butylester by treating with dicyclohexylcarbodiimide/tBuOH or Oxalylchloride/t-BuOH. Catalytic hydrogenation of the diene ester VIII with10% pd/C furnished the desired synthons, 4-aminophenylalkanoic ester IX.t-Butyl 4-(4-aminophenyl)-butyrate IX b was made in 64% yield from4-(p-nitrophenyl)-butyric acid by esterification followed by catalytichydrogenation. Treatment of the fatty acid synthons IX with X in DMA at80-100° C. followed by deprotection of the resulting coupled product XIwith trifluoroacetic acid (hereinafter referred to as TFA) containinganisole furnished the PMDTA fatty acid analogs of formula XII.

Compounds of formula II (B (hereinafter sometimes referred to as DP-MDTAanalogs) wherein

and R₆ and n are as defined above are prepared as shown in Scheme 2 byreacting the MDTA-chloride X with ω-aminoalkanoic acids or their1,1-dimethylethyl esters in DMA to obtain the amides of formula XIII orformula XIII′.

wherein n and R₆ are as defined above.

The compounds of formula III

wherein

n, m, R₁, R₂, R₃, R₄, R₅ and R₈ are as defined above, were prepared asshown in Scheme 3.

As an example, methyl oleate XIV was subjected to the Ritter reactionwith p-nitrobenzonitrile XIV in the presence of SnCl₄ at 50° C. toobtain the phenylamido adduct XVI. Catalytic hydrogenation of XVI (10%Pd/C in MeOH—EtOAc) provided the key aniline XVII. Treatment of XVIIwith MDTA-chloride X followed by basic hydrolysis furnished a desiredcompound of formula XVIII. Similarly, starting from appropriateunsaturated fatty acids of various chain lengths, other compounds offormula XVIII could be prepared.

The compounds of formula III wherein

wherein m, n, p and R₇ are as defined above, were prepared as shown inScheme 4.

As an example, methyl oleate XIV was reacted with 7-bromoheptanenitrilcin the presence of SnCl₄ and water at 50° C. for 40 h to obtain theamide XIX. Further treatment of XIX with NaN₃ in DMF gave thecorresponding azide XXa, which upon catalytic hydrogenation provided theamine XXb. Coupling of XXb with MDTA-chloride X in DMA followed by basichydrolysis furnished the desired compound of formula XXI.

The following working examples will further illustrate the compounds ofthe present invention. The highlighted numerals in the Examples refer tocompounds and moieties used in the Schemes.

Example 1 3,5-Bis-(Acetylmethylamino)-2,4,6-triiodobenzoic acid (I′)(Scheme 1) MDTA)

METHOD A

To a solution of 3,5-bis-(acetylamino)-2,4,6-triiodobenzoic acid(diatrizoic acid)(IV)(6.14 g, 10 mmol) in 6.5 N aq. NaOH (10 ml) andmethanol (10 ml), was added methyl iodide (7.1 g, 50 mmol) over a 5 minperiod, and the mixture was stirred at RT overnight (18 h). The mixturewas acidified to pH 5 with con. HCl, then diluted with cold water (100mL). The N-bis-methylated diatrizoic acid I′, thus precipitated as anamorphous white solid, was collected by filtration, washed with coldwater and dried; yield 5.06 g (79%).

Elemental analysis: Calc'd for C₁₃H₁₃I₃N₂O₄, 0.15 H₂O: C 24.22; H, 2.08;N, 4.35; I, 59.06; O, 9.97; Found: C, 23.80; H, 2.22; N, 4.11; I, 58.86;H₂O, 0.41 (KF)

Method B

A solution of dimethylsulfate in acetone (200 mL) was slowly added indrops to a stirred solution of diatrizoic acid IV (100 g, 163 mmol) in5N KOH (200 mL) and water (100 mL) at 0-15° C. Following the addition,the mixture was stirred at RT for 44 h. Acetone was removed and themixture acidified with concentrated HCl. The precipitated white solidwas collected by filtration, washed with water, CH₂Cl₂, EtOAc and water.This solid upon crystallization from ETOAc/EtOH furnished pure MDTA I′as a white solid (45 g, 43%), which was identical with the productprepared by method A.

Example 2 3,5-Bis-(Acetylmethylamino)-2,4,6-triiodobenzene carbonylchloride (X) (Scheme 1) (MDTA-Cl)

A mixture of 3,5-bis-(acetylmethylamino)-2,4,6-triiodobenzoic acid I′(1.28 g, 2 mmol) and thionyl chloride (20 mL) was stirred under reflux(bath temperature 100° C.) under nitrogen for 20 h. The excess thionylchloride was removed under vacuum, and the residue triturated with ethylacetate (20 mL) for 15 min. The desired acid chloride X, formed as awhite amorphous solid, was collected by filteration and dried. Yield0.95 g (70%).

Elemental analysis: Calc'd for C₁₃H₁₂N₂O₃ClI₃ 1.02 H₂O: C,23.00; H,2.08; N, 4.13; O: 9.48, Cl:5.22, I:57.67. Found: C, 23.06; H, 1.78; N,4.07; O: NA, Cl:5.26, I:56.45.

Example 34-(((3,5-Bis(Acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)-benzeneaceticacid (XIIa) (Scheme 1)

A mixture of MDTA-Cl X (2.18 g, 3.3 mmole) and p-aminophenylacetic acid(1.2 g, 8.27 mmole) in DMA (8 mL) was stirred at 60° C. for 30 h. Thesolvent was removed and the residue was treated with hot EtOAc (600 mL)containing EtOH (25 mL). The solution was filtered and the filtrate wasfreed of the solvent. The solid was recrystallized from EtOAc-EtOH toafford the title compound as a white amorphous solid (1.54 g, 57%).

Elemental analysis: Calc'd for C₂₁H₂₀N₃I₃. 0.66 H₂O: C 32.05; H, 2.73;N, 5.34; I, 48.38; O, 11.50. Found: C,32.34; H, 2.42; N, 5.05; I,48.48%.

Example 44-(((3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid (XIIb) (Scheme 1) a. 4-Aminobenzenebutyric acid 2,2-dimethylethylester (IXb)

4-(p-Nitrophenyl)butyric acid (4.18 g, 20 mmol) was treated with oxalylchloride at RT for 24 h to obtain the corresponding acid chloride, whichwas reacted with t-butanol (18.5 g, 250 mmol) in the presence oftriethylamine (4 g, 40 mmol) at 0-5° C. to get the desired t-butyl ester(3.5 g, 66%). Hydrogenolysis of the nitro-ester (3 g) over 10%Pd/C inethanol yielded the amino-cster IXb (3.0 g).

b. 4-(((35-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid 2,2-dimethylethyl ester) (XIb)

To a solution of 4-aminobenzenebutyric acid 2,2-dimethylethyl ester IXb(2.0 g, 7.5 mmol) in dimethylacetamide (DMA 25 mL), was added 3,5bis(acetylmethylamino)-2,4,6 triiodobenzoyl chloride X (1.98 g, 3 mmol),and the mixture stirred at 90-95° C. for 6 h. The solvent was removed invacuo and the residue was dissolved in ethyl acetate (200 mL). Theorganic extract was washed with saturated sodium bicarbonate (250 mL),water and saturated sodium chloride and dried over sodium sulfate. Thesolvent was removed in vacuum and the residue purified by a silica gelcolumn (150 g) using hexane/EtOAc to obtain the title compound XIb (1.98g, yield 74%). (MS: m/e 858 (M−H)⁻.

c.4-(((3.5-Bis(acetylmethylamino)-2,4.6-triiodophenyl)carbonyl)amino)benzenebutyricacid (XIIb)

To the t-butylester XIb (1.98 g) were added anisole (6 mL) and TFA (20mL) and the solution was stirred at room temperature for overnight. Thesolution was evaporated to dryness and trace amounts of anisole and TFAwere removed by repeated evaporating with water to give a solid (1.78 g,99%). The solid was recrystallized from EtOH—EtOAc to obtain the pureXIIb. (MS: m/e 804 [M+H]⁺

Elemental analysis: Calc'd for C H N₃I₃O₅: C 34.18; H, 3.06; N, 5.20; I,47.11. Found: C,34.38; H, 2.84; N, 5.0; I, 46.69.

Example 54-[[[3,5-Bis(acetylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneheptanoicacid (XIIc) (Scheme 1) a. 4-Aminobenzenehcptanoic acid 1,1-dimethylethylester (IXc)

To a solution of 7-(4-nitrophenyl)4,6-heptadicnic acid, 1,1-dimethylester (0.6 g, 1.98 mmol, 1.0 equiv.) in methanol (50 mL) and ethylacetate (5 mL) was added 10% Pd/C (0.5 g). The mixture was hydrogenatedat 50 psi for 55 h. The catalyst was filtered off. The filtrate wasconcentrated to dryness and the residue was purified by chromatographyover a silica gel column to afford pure IXc (0.46 g, 84%). MS: m/e 278(M+H)⁺

b.4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzeneheptanoicacid 1,1-dimethylethyl ester (XIc)

To a solution of 4-aminobenzeneheptanoic acid 2,2-dimethylethyl esterIXc (185 mg, 0.67 mmol) in dimethylacetamide (DMA, 5 mL), was added3,5-bis(acetylmethylamino)-2,4,6-triiodobenzoyl chloride X (220 mg, 0.33mmol), and the mixture was stirred at 90-95° C. for 6 h. The solvent wasremoved in vacuo, and the residue was taken up in ethyl acetate (60 mL).The ethyl acetate solution was washed with cold aq. NaHCO₃ followed bywater and saturated NaCl solution, and dried over sodium sulfate.Removal of the solvent gave a brown solid (0.6 g) which was purified bycolumn chromatography over silica gel (40 g) using hexane/EtOAc toobtain the carboxamide XIc as an amorphous solid; yield 148 mg (50%).

c.4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzeneheptanoicacid (XIIc)

To a solution of the t-butyl ester XIc obtained in Example 5b (125 mg,0.14 mmol) in anisole (1 mL) was added trifluoroacetic acid (4 mL) andthe solution was stirred at RT for 12 h. The solvents were removed invacuo, and the residue was triturated with hexane (10 mL). The hexaneswere removed to give a semi solid (125 mg) which was crystallized fromethyl acetate (3-4 mL) to furnish the title compound XIIc as a whiteamorphous solid (60 mg, yield 52%).

Elemental analysis: Calc'd for C₂₆H₃₀I₃N₃O₅ (845.22): C, 36.95; H, 3.58;N, 4.97; I, 45.04; O, 9.46. Found: C, 36.99; H, 3.31; N, 4.62; I,44.86%.

Example 64-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]amino]-benzeneundecanoicacid (XIId) a. 4-Aminobenzeneundecanoic acid 1,1-dimethylethyl ester(IXd)

To a solution of 11-(4-nitrophenyl)8-10-undecadienoic acid 1,1-dimethylester (2.0 g, 5.57 mmol, 1.0 equiv.) in methanol (100 ml) and ethylacetate (15 ml) was added 10% Pd/c (0.5 g). The mixture was hydrogenatedat 50 psi for 24 h. The catalyst was filtered off. The filtrate wasconcentrated to dryness to give 1.7 g 95.4% yield) of the crude productwhich upon purification by a silica gel column (CH₂Cl₂:hexane 1.5:1)gave 1.35 g (73% yield) of pure compound.

Microanalysis: Cal'd for C₂₁H₃₅NO₂: C:75.63, H:10.58, N:4.20, O:9.59.Found: C: 75.56, H: 10.68, N: 4.63, O:NA.

b.4[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzeneundecanoicacid 1,1-dimethylethyl ester (XId)

To a solution of 4-aminobenzeneundecanoic acid 2,2-dimethylethyl esterIXd (0.5 g, 1.5 mmol) in dimethyl acetamide (DMA, 5 mL), was added3,5-bis(acetylmethylamino)-2,4,6-triiodobenzoyl chloride X (0.34 g, 0.55mmol), and the mixture was stirred at 100° C. for 5 h. The solvent wasremoved in vacuo, and the residue was taken up in ethyl acetate (60 mL).The ethyl acetate solution was washed with cold aq. NaHCO₃ followed bywater and saturated NaCl solution, and dried over sodium sulfate.Removal of the solvent gave a brown solid (0.76 g) which was purified bycolumn chromatography over silica gel (40 g) using hexane-ethyl acetateto obtain the carboxamide XId as an amorphous solid; yield 0.28 g (58%).

Elemental analysis: Calc'd for C₃₄H₄₆N₃I₃O₅ (957.5): C, 42.65; H, 4.84;N, 4.39; I, 39.76; O, 8.36; Found: C, 42.78; H, 4.92; N, 4.52; I,39.61%.

c.4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzeneundecanoicacid (XIId)

To a solution of the t-butyl ester XId of Example 6b (180 mg, 0.188mmol) in anisole (1 mL) was added trifluoroacetic acid (5 mL) and thesolution was stirred at RT for 12 h. The solvents were removed in vacuo,and the residue was triturated with hexane (10 mL). The hexanes wereremoved to give a semi solid (175 mg) which was crystallized form ethylacetate (3-4 mL) to furnish the title compound XIId as a white amorphoussolid (147 mg, yield 87%).

Elemental analysis: Calc'd for C₃₀H₃₈N₃I₃O₅ H₂O(0.43): C, 39.64; H,4.31; N, 4.62; I, 41.88; O, 9.55. Found: C, 39.75; H, 4.19; N, 4.51; I,41.69, H₂O 0.85%.

Example 74[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzenepentadecanoicacid (XIIe) (Scheme 1) a. [4-Aminobenzenepentadecanoic acid1,1-dimethylethyl ester (IXe)

To a solution of 15-[4-nitrophenyl] 12,14-pentadecienoic acid,1,1-dimethylethyl ester (1.40 g, 3.4 mmol) in methanol (80 ml) and ethylacetate (20 ml) was added 10% Pd/C (0.3 g). The mixture was hydrogenatedat 50 psi for 20 h. The catalyst was filtered off. The filtrate wasconcentrated to dryness and to give 1.28 g (97.5% yield) of the crudeproduct, which was purified by a silica gel column to obtain IXe (1.08 g(82.3% yield). MS: m/e 390 (M+H)⁺.

b. 4-[[[3,5-Bis(acetylmcthylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzenepentadecanoicacid 1,1-dimethylethyl ester (XIe)

To a solution of 4-aminobenzenepentadecanoic acid 2,2-dimethyl ester IXeof Example 7a (430 mg, 1.1 mmol) in dimethylacetamide (DMA, 10 mL), wasadded 3,5-bis(acetylmethylamino)-2,4,6-triiodobenzoyl chloride X (365mg, 0.55 mmol), and the mixture was stirred at 100° C. for about 5 h.The solvent was removed in vacuo, and the residue was taken up in ethylacetate (60 mL). The ethyl acetate solution was washed with cold aq.NaHCO₃ followed by water and saturated NaCl solution, and dried oversodium sulfate. Removal of the solvent gave a brown solid (0.78 g) whichwas purified by column chromatography over silica gel (60 g) usinghexane-ethyl acetate to obtain the carboxamide XIe as an amorphoussolid; yield 360 mg (65%).

Elemental analysis: Calc'd for C₃₈H₅₄N₃I₃O₅ (1013.53): C, 45.03; H,5.37; N, 4.15; I, 37.56; O, 7.89; Found: C, 44.62, H, 5.23; N, 4.15; I,37.54%.

c.4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzenepentadecanoicacid (XIIe)

To a solution of4-[[[3,5-bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepentadecanoicacid, 1.1-dimethylethyl ester XIe of Example 7b (30 mg, 0.3 mmol) inanisole (1 mL), was added trifluoroacetic acid (10 mL) and the mixturestirred at RT overnight (15 h). The solvents were removed in vacuo, andthe residue crystallized from ethyl acetate to furnish pure XIIe as awhite amorphous solid (205 mg, yield 70%, purity>98%). Additionalproduct (35 mg, purity 96%) was obtained from the mother liquor for atotal yield of 81%.

Elemental analysis: Calc'd for C₃₄H₄₆N₃I₃O₅ (957.5): C, 42.65; H, 4.84;N, 4.39; I, 39.76; O,8.36; Found: C, 42.67; H, 4.89; N, 4.42; I, 39.55%.

Example 84-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzenepentadecanoicacid (XIIf) (Scheme 1) a. 19-[4-Aminobenzene nonadecanoic acid1,1-dimethylethyl ester (IXf)

To a solution of 19-[4-nitrophenyl] 16,18-nonadecadienoic acid,1,1-dimethylethyl ester (1.45 g, 3.09 mmol, 1.0 equiv.) in methanol (30ml) and ethyl acetate (30 ml) was added 10% Pd/C (0.46 g). The mixturewas hydrogenated at 50 psi for 20 h. The catalyst was filtered off. Thefiltrate was concentrated to dryness to give 1.32 g (94% yield) of thecrude product, which was purified by a silica gel column to give 0.85 g(62% yield) of the pure product IXf.

Elemental Analysis: C₂₉H₅₁NO₂, C: 78.15, H: 11.53, N: 3.14, O: 7.18.Found: C: 78.18, H: 11.46, N: 3.07.

b.4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzenepentadecanoicacid 1,1-dimethylethyl ester (XIf)

To a solution of 4-aminobenzene-nonadecanoic acid 2,2-dimethylethylester IXf (356 mg, 0.8 mmol) in dimethylacetamide (DMA, 3 mL), was added3,5-bis-(acetylmethylamino)-2,4,6-triiodobenzoyl chloride X (264 mg, 0.4mmol), and the mixture was stirred at 100° C. for about 6 h. The solventwas removed in vacuo, and the residue was taken up in ethyl acetate (60mL). The ethyl acetate solution was washed with cold aq. NaHCO₃ followedby water and saturated NaCl solution, and dried over sodium sulfate.Removal of the solvent gave a brown solid (605 mg) which was purified bycolumn chromatography over silica gel to obtain the carboxamide titlecompound XIf as an amorphous solid (258 mg, yield 60%).

Elemental analysis: Calc'd for C₄₂H₆₂N₃I₃O₅ (1069.64): C, 47.16; H,5.84; N, 5.84; I, 35.59; O, 7.48; Found: C, 47.10, H, 5.88; N, 3.76; I,34.42%.

c. 4-[8[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenenonadecanoicacid (XIIf)

To a solution of the t-butyl ester XIf (182 mg, 0.17 mmol) in anisole (1mL) was added trifluoroacetic acid (5 mL) and the solution was stirredat RT for 12 h. The solvents were removed in vacuo, and the residue wastriturated with hexane (10 mL). The hexanes were removed to give a semisolid (170 mg) which was crystallized from ethyl acetate (3-4 mL) tofurnish the title compound XIIf as a white amorphous solid (126 mg,yield 73%).

Elemental analysis: Calc'd for C₃₈H₅₄N₃I₃O₅: C, 45.03; H, 5.37; N, 4.15;I, 37.56; O, 7.89; Found: C, 44.86; H, 5.41; N, 4.22; I, 39.93%.

Example 94-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-aceticacid (XIIIa)

To a mixture of aminoacetic acid 1,1-dimethylethyl ester (glycinet-butyl ester) HCl salt (1.1 g, 6.6 mmol) in DMA (20 mL) andtriethylamine (1.38 mL, 9.9 mmol, 4.5), was added MDTA-Cl X (1.45 g),2.2 mmol). The mixture was stirred at 80° C. for 4 h. DMA was removed invacuo and the crude product was purified by a silica gel chromatography(EtOAc/hexane 3:7) to give pure carboxamide 1.22 g (74%). This productwas treated with TFA (24 mL) and anisole (2.3 mL) for 6 h at RT. Thesolvents were removed. The product was washed with hexane and water. Thecrude was recrystallized from EtOAc/hexane to furnish the pure titlecompound XIIIa (0.94 g, 83%).

Elemental analysis: Calc'd for C₁₅H₁₆N₃O₅I₃: 0.2 EtOAc: C, 26.48; H,2.48; N, 5.86; O, 12.06; I,53.12; Found: C, 26.55; H, 2.40; N,6.06; I,52.88%.

Example 104-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-butanoicacid (XIIIb)

To a mixture of MDTA-Cl (X) (2.0 g, 3 mmol) in DMA (10 mL) was added4-aminobutanoe acid (0.93 g, 9 mmol) at 0-15° C. The mixture was stirredat RT for 40 h. DMA was removed in vacuo and water was added. Then thecrude product that separated out was collected and recrystallized fromEtOAc/EtOH) to give the title compound XIIIb (0.54 g, 25%). The aqueoussolution, upon chromatography over a CHP-20 column furnished additionalproduct (0.43 g (total yield 0.97 g, 45%).

Elemental analysis: Calc'd for C₁₇H₂₀N₃O₅I₃: 0.35 H₂O: C, 37.84; H,2.84; N, 5.73; O, 11.66; I, 51.92; Found: C, 28.19; H, 2.85; N, 5.47; I,52.01%.

Example 114[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-heptanoicacid (XIIIc)

To a solution of 7-aminoheptanoic acid (0.8 g, 5.5 mmol) in DMA (20 mL)was added MDTA-Cl (X) (2.8 g, 4.2 mmol) and the mixture stirred at 80°C. for 24 h. DMA was removed. To the residue water was added. The solidmaterial was collected and recrystallized from EtOH to furnish the puretitle compound XIIIc (1.02 g, 31%).

Elemental analysis: Calc'd for C₂₀H₂₆N₃O₅I₃: 0.18 EtOAc: C, 31.70; H,3.52; N, 5.35; O, 10.92; I, 48.50; Found: C, 31.70; H, 3.13; N, 5.28; I,48.49%.

Example 124-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-dodecanoicacid (XIIId)

To a solution of 12-aminododecanoic acid (1.1 g, 4.9 mmol) in DMA (25mL) was added MDTA-Cl (X) (2.5 g, 3.8 mmol) and the mixture stirred at80-85° C. for 39 h. DMA was removed and the product was purified by aCHP-20 column to furnish the pure title compound XIIId (1.6 g, 50%).

Elemental analysis: Calc'd for C₂₅H₃₆N₃O₅I₃: 0.33 H₂O: C, 36.31; H,4.57; N, 4.77; O, 11.16; I, 43.20; Found: C, 36.71; H, 4.29; N, 4.86; I,43.58%.

Example 139(10)-N-(4-(((3,5-bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]benzoyl)amino-octadecanoicacid (XVIII) a. Methyl 9/10[p-nitrobenzoylamino]octadecanoate (XVI)

To a mixture of methyl oleate XIV (592 mg, 2 mmol) andp-nitrobenzonitrile XV (296 mg, 2 mmol), was added SnCl₄ (572 mg, 2.4mmol) followed by water (43 mg, 2.4 mmol). The mixture was stirred at50-60° C. for 70 h. This was taken up in ether (200 mL) and washed withwater followed by aq. NaHCO₃ solution. The organic extract was dried andconcentrated to yield a brownish solid (0.9 g). The material waspurified by flash chromatography over a column of silica gel elutingwith gradient hexane/ethyl acetate to obtain methyl9/10[p-nitrobenzamido]octadecanoate XVI as a white solid (620 mg, 67%).MS: m/e 463 (M+H)⁺.

b. Methyl 9/10[p-aminobenzoylamino]octadecanoate (XVII)

Methyl 9/10[p-nitrobenzamido]octadecanoate XVI of Example 13a (5.08 g,11 mmol) was dissolved in a mixture of EtOAc/EtOH (2:1) (100 mL) and thesolution was purged with nitrogen. After the addition of 10% Pd/C (0.5g), the mixture was hydrogenated at 50 psi for 24 h. The catalyst wasfiltered off, and the filtrate was concentrated to furnish thecorresponding amine XVII as a highly viscous oil (4.74 g, 99%). MS: m/e433 (M+H)⁺.

c.9(10)-N-(4-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzoyl)amino-octadecanoicacid (XVIII)

A mixture of MDTA-Cl X and 9(10)-octadecanoate analog XVII of Example13b in DMA was stirred at 60° C. for 30 h, and then at 80° C. for 15 h.The solvent was removed and the product was purified by columnchromatography. This product was then treated with 10% aq. methanolicKOH overnight. The mixture was acidified and the solid was collected.Recrystallization from ethanol furnished the pure compound XVIII as awhite solid (0.53 g; 76% yield). MS: m/e 1043 (M+H)⁺.

Elemental analysis: Calc'd for C₃₈H₅₃N₄O₆I₃ C: 43.78; H: 5.12; N: 5.37;O: 9.21, I: 36.52. Found: C: 43.98, H: 5.25, N: 5.17, I: 36.86.

Example 149(10)-N-(7-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)heptanoyl)amino-octadecanoicacid (XXI) a. Methyl 9(10)-(7-bromoheptanoylamino)-octadecanoate (XIX)

Methyl oleate XIV (2.9 g, 10 mmol) was treated with7-bromoheptanenitrile (1.9 g, 10 mmol) and water (0.2 mL, 11 mmol). Themixture was stirred at room temperature for 10 min and then at 50° C.for 40 h. The mixture was dissolved in EtOAc and washed with aqueousNaHCO₃ and water. The organic extract was concentrated and the residuewas purified by silica gel chromatography to obtain pure XIX (3.02 g,60%). MS: m/e 506, 504 (M+H)⁺.

b. Methyl 9(10)-(7-Azidoheptanoylamino)-octadecanoate (XXa)

A mixture of bromoheptanoyl derivative XIX (2.92 g, 5.8 mmol) and NaN₃(0.74 g, 11.6 mmol) in DMF (15 mL) was stirred at 50° C. for 40 h. Thesolvent was removed in vacuo and the residue was redissolved in EtOAc.The organic extract was washed with water, dried, and concentrated. Theresidue was purified by silica gel chromatography to afford pure azideXXa (2.2 g, 81.4%). MS: m/c 467 (M+H)⁺.

c. Methyl 9(10)-(7-aminoheptanoylamino)-octadecanoate (XXb)

A solution of the above azide XXa (21 g, 4.5 mmol) in MeOH was stirredwith Lindlar catalyst (5% Pd/CaCO₃) (1.04 g) under 1 atmosphere ofhydrogen at RT for 20 h. The catalyst was filtered off and the filtratewas concentrated. The crude product was purified by silica gelchromatography to obtain the corresponding pure amine XXb (1.78 g, 90%yield). MS: m/e 440 (M+H)⁺.

d.9(10)-N-(7-(((3.5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)heptanoyl)amino-octadecanoicacid (XXI)

A mixture of MDTA-Cl (X) (1.32 g, 2 mmol) and 9(10)-methyl(7-aminoheptanoylamino)octadecanoate derivative XXb (1.8 g, 4.2 mmol) inDMA was stirred at 80° C. for 24 h. The solvent was removed and theproduct was purified by silica gel column chromatography to obtain theester intermediate (0.8 g, (38%). This product was then treated with 10%aq. methanolic KOH overnight. The mixture was acidified and the obtainedsolid was collected. Recrystallization from ethanol furnished the titlecompound XXI (0.53 g, 76%).

Elemental analysis: Calc'd for C₃₈H₅₃N₄O₆I₃: (1042): C, 43.78; H, 5.12;N, 5.37; I, 36.52; O, 9.21; Found: C, 43.98; H, 5.25; N,5.17; I, 35.86%.

RADIO LABELING

Radioiodination

All of the new analogs were radiolabeled in order to determine theirphysical and biological properties. The iodinated compounds wereexchange-labeled by heating with Na¹²⁵I in the presence of CuSO₄ andNa₂S₂O₅ in glacial acetic acid at 135-150° C. for 1 h, followed by HPLCpurification using a nucleosil C18 column and CH₃CN—H₂O containing 0.1%TFA as an eluent. In some cases (e.g. the compound of Example 12) theradioiodination was carried out by heating with Na*I in HOAc—NaOAc (pH4.6) at 100° C. for 15 min. In all cases radiolabeled compounds ofacceptable radiochemical purity and specific activity were obtained.

The compound of formula I, N,N-dimethyl-diatrizoic acid, was similarlyradiolabeled for biological studies.

Vehicles Used For Incorporating the Compounds of the Present Invention

a) For intravenous administration the preferred vehicle for thecompounds of formula I, II and III is bovine serum albumin, however,other physiologically acceptable vehicles may also be used.

b) For oral and rectal administration the compounds of formula I, II andIII are incorporated in physiologically acceptable carriers orexcipients in a manner within the skill of the art.

The compounds with the addition of pharmaceutically acceptable aids(such as surfactants and emulsifiers) and excipients may be suspended orpartially dissolved in an aqueous medium resulting in a dispersion,solution or suspension. However, the oily contrast agents arc preferablymade into emulsions.

Compositions of the present invention typically comprise the followingpharmaceutically acceptable components based on % w/v:

Non aqueous phase 1-50

Contrast Agent 0.001-75

Excipient 0-20

Aids/Surfactants/Emulsifiers 0.01-15

water q.s. to 100

The nonaqueous phase comprises vegetable oils such as safflower oil;non-metabolizing fat substituents, such as Simplesse; fluorinatedhydrocarbons, such as perfluorodecalin; mineral oil and simethicone.

Excipients advantageously used in the formulations include viscositymediating and stabilizing agents, such as microcrystalline cellulose,methylcellulose, hydroxypropyl methylcellulose and gum arabic.Physiologically acceptable substances may also be included, such assodium citrate, sodium chloride, therapeutic substances, antacidsubstances and flavoring agents. The inclusion ofantimicrobial/antiseptic agents such as methyl parahydroxybenzoate,ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, benzoic acid orsorbic acid may also be desirable in some formulations.

As known by those skilled in the art, surfactants or emulsifiers canreduce the interfacial tension between two immiscible phases, i.e.oil-in-aqueous medium. These agents can be used alone or in combinationwith other emulsifying agents and surfactants. For example, Dow CorningMedical Antifoam AF, which is a composition of 30% w/vpolydimethylsiloxane (simethicone) and silica aerogel, 14% w/v stearateemulsifiers and 0.075% w/v sorbic acid, the balance being water, may beused by itself. Intralipid, which is an emulsion of fatty acids needsthe presence of a suspending agent for it to form an acceptable emulsionwith contrast agents of the present invention. The amount of suchsurfactants may be in the range of form 0.01 to 15% w/v of the aqueousformulations, although the amount, in general, is kept as low aspossible, preferably in the range of 0.05 to 5% w/v. The surface activeagents may be cationic, anionic, nonionic, zwitterionic or a mixture oftwo or more of these agents.

Suitable cationic surfactants include cetyl, trimethyl ammonium bromide.Suitable anionic agents include sodium lauryl sulphate, sodiumheptadecyl sulphate, alkyl benzenesulphonic acids and salts thereof,sodium butylnapthalene sulfonate and sulphosuccinates.

In preparing the formulations of the present invention we prefer to usenonionic emulsifiers or surface active agents. In the nonionicemulsifying agents the proportions of hydrophilic and hydrophobic groupsare about evenly balanced. They differ from anionic and cationicsurfactants by the absence of charge on the molecule and, for thatreason, are generally less of an irritant than the cationic or anionicsurfactants. Nonionic surfactants include carboxylic esters, carboxylicamides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols.

The dosages of the present invention will be in the range of from about0.1 to about 16.0 g iodine/kg body weight, preferably in the range offrom about 0.5 to about 6.0 g iodine/kg body weight, and most preferablyin the range of from about 1.2 to about 2.0 g iodine/kg body weight forregular x-ray visualization of the GI tract. For CT scanning, thecontrast agents of the present invention will be in the range of fromabout 1 to about 600 mg iodine/kg body weight, preferably in the rangeof from about 20 to about 200 mg iodine/kg body weight, and mostpreferably in the range of from about 40 to about 80 mg iodine/kg bodyweight.

The concentration of the contrast agent should be in the range of fromabout 0.001% w/v to about 75% w/v of the formulation, preferably fromabout 0.05% w/v to about 50% w/v and most preferably of from about 0.1%to about 20% w/v.

Biodistribution studies were conducted in mice and the results are givenin Table I. X-Ray CT images of MDTA in mice and rats indicate that thesehydrophobic diatrizoate analogs may be of promise for liver imaging.

TABLE I Biodistribution of MDTA, P-MDTA and DP-MDTA in MICE # (%ID/g-tissue) Sm/Lrg. Blood Kidney Liver Intestine # Compound 1′ 5′ 60′1′ 5′ 60′ 1′ 5′ 60′ 1′ 5′ 60′ Remarks 1 MDTA 4.56 1.21 0.00 37.57 21.500.18 15.75 15.40 0.85 1.50 4.55 13.35 Tracer level MDTA-Na 6.21 3.030.16 12.97 12.72 0.96 13.23 17.56 2.42 1.81 3.92 17.02 0.18M MDTA-NMG6.63 3.66 0.12 13.53 12.65 0.81 12.30 16.23 2.13 2.03 3.80 16.48 0.19M 2F2-P-MDTA 4.83 0.96 0.04 11.48 5.83 0.33 17.88 12.87 2.25 2.47 9.5425.42 All tracer level 3 F4-P-MDTA 3.55 0.57 0.07 5.63 5.41 0.63 29.6529.45 6.13 1.71 4.56 20.43 4 F7-P-MDTA 2.38 0.57 0.15 4.28 2.94 0.3039.53 37.19 5.02 1.38 6.20 26.75 5 F11-P-MDTA 9.14 0.74 0.08 6.21 3.630.10 57.93 60.13 2.96 1.14 3.06 38.21 6 F15-P-MDTA 24.65 4.28 0.12 8.285.10 0.34 46.37 76.33 6.18 2.13 4.85 43.68 7 F19-P-MDTA 36.72 13.17 0.685.56 5.45 2.67 17.24 24.68 10.41 1.05 2.40 14.41 8 F2-DP-MDTA 4.57 0.810.03 17.07 5.69 0.16 12.75 10.60 1.03 1.28 8.81 16.47 9 F4-DP-MDTA 4.910.82 0.12 17.91 7.89 0.05 16.11 11.91 0.33 1.73 11.33 21.17 10F7-DP-MDTA 2.44 0.57 0.05 9.50 8.33 0.16 17.05 9.81 0.77 4.92 14.4722.19 11 F12-DP-MDTA 2.38 0.39 0.04 9.89 5.72 0.07 28.89 16.56 2.17 2.2811.62 28.01 12 9/10-F-18P-MDTA 6.16 0.46 0.26 3.32 2.09 0.39 30.29 32.333.16 0.51 2.71 20.21

Having described the invention, it is understood that changes andmodifications may be effected within spirit and scope of the invention.

What is claimed is:
 1. A compound of formulae II or III or apharmaceutically acceptable salt thereof,

R₁, R₅, R₇ and R₈ are the same or different and are hydrogen, alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, haloalkyl, hydroxyalkyl,alkoxyalkyl, carboxyalkyl or carboxamido alkyl; R₂ and R₃ are hydrogen;R₃ and R₄ are methyl; n is 2 or 3; and m and p are the same or differentand are 0-24 with the proviso that m+n≦24.
 2. A compound according toclaim 1 wherein said cycloalkyl is substituted with at least onesubstituent selected from the group consisting of alkyl, halogen,hydroxy, hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy,carbamoyl, alkoxycarbonyl, alkylsulfonyl and sulfonamido.
 3. A compoundaccording to claim 1 wherein said aryl is phenyl, pyridyl, furanyl,thiophenyl, pyrrolyl or imidazolyl.
 4. A compound according to claim 3wherein said aryl is substituted with at least one moiety selected fromthe group consisting of halogen, nitroamino, maleimido, isothiocyanato,hydroxy, hydroxyalkyl, alkyl, alkoxy, carbamoyl, carboxamide, acylaminoand carboxy.
 5. The compound according to claim 1 selected from thegroup consisting of:4-(((3,5-Bis(Acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzeneaceticacid;4-(((3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid 1,1-dimethylethyl ester;4-(((3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triodopheny]carbonyl]amino]-benzeneheptanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneheptanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneundecanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodopheny]carbony]amino]-benzeneundecanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepenta-decanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepenta-decanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzene-nonadecanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzene-nonadecanoicacid;9(10)-N-(4-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzoyl)amino-octadecanoicacid;9(10)-N-(4-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)-benzoyl)amino-octadecanoicacid methyl ester;9(10)-N-(7-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)-heptanoyl)amino-octadecanoicacid;9(10)-N-(7-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)-heptanoyl)amino-octadecanoicacid, methyl ester; 4-Aminobenzenebutyric acid 1,1-dimethylethyl ester;4-Aminobenzeneheptanoic acid 1,1-dimethylethyl ester;4-Aminobenzeneundecanoic acid 1,1-dimethylethyl ester;4-Aminobenzenepentadecanoic acid 1,1-dimethylethyl ester; and4-Aminobenzenenondecanoic acid 1,1-dimethylethyl ester.
 6. Methyl9/10[p-nitrobenzoylamino]octadecanoate.
 7. Methyl9/10[p-aminobenzoylamino]octadecanoate.
 8. Methyl9(10)-(7-bromoheptanoylamino)octadecanoate.
 9. Methyl9(10)-(7-azidoheptanoylamino)octadecanoate.
 10. Methyl9(10)-(7-aminoheptanoylamino)octadecanoate.
 11. An x-ray contrastcomposition comprising a compound of formulae II or III or apharmaceutically acceptable salt thereof,

R₁, R₅, R₇ and R₈ are the same or different and are hydrogen, alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl, haloalkyl, hydroxyalkyl,alkoxyalkyl, carboxyalkyl or carboxamido alkyl; R₂ and R₃ are hydrogen;R₃ and R₄ are methyl; n is 2 or 3; and m and p are the same or differentand are 0-24 with the proviso that m+n≦24 in a pharmaceuticallyacceptable vehicle.
 12. The x-ray contrast composition of claim 11wherein said cycloalkyl is substituted with at least one substituentselected from the group consisting of alkyl, halogen, hydroxy,hydroxyalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,dialkylamino, alkanoylamino, thiol, alkylthiol, nitro, cyano, carboxy,carbamoyl, alkoxycarbonyl, alkylsulfonyl and sulfonamido.
 13. The x-raycontrast composition of claim 11 wherein said aryl is phenyl, pyridyl,furanyl, thiophenyl, pyrrolyl or imidazolyl.
 14. The x-ray contrastcomposition of claim 13 wherein said aryl is substituted with at leastone moiety selected from the group consisting of halogen, nitroamino,maleimido, isothiocyanato, hydroxy, hydroxyalkyl, alkyl, alkoxy,carbamoyl, carboxamide, acylamino and carboxy.
 15. The x-ray contrastcomposition of claim 11 wherein said compound is selected from the groupconsisting of:4-(((3,5-Bis(Acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzeneaceticacid;4-(((3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid 1,1-dimethylethyl ester;4-(((3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzenebutyricacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneheptanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneheptanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneundecanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzeneundecanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepenta-decanoicacid;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepenta-decanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzene-nonadecanoicacid 1,1-dimethylethyl ester;4-[[[3,5-Bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzene-nonadecanoicacid9(10)-N-(4-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)benzoyl)amino-octadecanoicacid;9(10)-N-(4-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)-benzoyl)amino-octadecanoicacid methyl ester;9(10)-N-(7-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)heptanoyl)amino-octadecanoicacid; and9(10)-N-(7-(((3,5-Bis-(acetylmethylamino)-2,4,6-triiodophenyl)carbonyl)amino)heptanoyl)amino-octadecanoicacid, methyl ester.
 16. A method for medical x-ray diagnostic imagingwhich comprises administering to the body of a mammal a contrasteffective amount of the x-ray contrast composition of claim
 11. 17. Themethod of claim 16 wherein said administration is oral administration.18. The method of claim 16 wherein said administration is intravenousadministration.
 19. The method of claim 16 wherein said medical x-raydiagnostic imaging is x-ray computed tomographic imaging.
 20. A methodfor medical x-ray diagnostic imaging which comprises administering tothe body of a mammal a contrast effective amount of the x-ray contrastcomposition of claim
 15. 21. The method of claim 15 wherein saidadministration is oral administration.
 22. The method of claim 15wherein said administration is intravenous administration.
 23. Themethod of claim 15 wherein said medical x-ray diagnostic imaging isx-ray computed tomographic imaging.
 24. A process of preparing acompound of the formula

comprising the steps of: a) reacting, in a dimethylacetamide solution, a(4-aminophenyl) alkanoic ester of the formula

wherein n is 0-24, with N,N-dimethyldiatrizoic acid chloride of theformula

to obtain the coupled compound of the formula

wherein n is 0-24; and b) deprotecting the coupled compound in atetrafluoroacetate-anisole mixture.
 25. A process for preparing acompound of the formula

comprising the steps of: a) hydrogenating a phenylamido compound of theformula

to obtain the aniline of the formula

wherein m and n are independently 0-24; R₁, R₂,R₃ and R₄ areindependently hydrogen, alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or carboxamido alkyl;b) condensing the aniline with N,N-dimethyldiatrizoic acid chloride ofthe formula

to obtain the adduct thereof; and c) hydrolyzing the adduct.
 26. Aprocess for preparing a compound of the formula

comprising the steps of: a) treating an amide of the formula

with NaN₃ in a dimethylformamide solution to obtain an adduct; and b)hydrogenating the adduct to obtain a compound of the formula

wherein m and n are independently 0-24, X is N₃ or NH₂, and R₁, R₂,R₃and R₄ are independently hydrogen, alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkylor carboxamido alkyl; c) condensing the hydrogenated compound withN,N-dimethyldiatrizoic acid chloride of the formula

in dimethylacetamide solution to obtain an adduct; and d) hydrolyzingthe adduct.